Vitamin D levels are declining among adults in the United States. The clinical consequences of these declines are unclear. Men and women with PAD have even lower levels of circulating vitamin D than those without PAD. Basic and animal research suggests that vitamin D is important for maintaining skeletal muscle health and function. However, associations of low vitamin D levels with functional decline in clinical populations without PAD remain unclear. Patients with PAD may be particularly susceptible to the adverse consequences of low vitamin D levels on skeletal muscle, because lower extremity ischemia is associated with adverse calf skeletal muscle characteristics which in turn promote functional decline in PAD. The primary aims of this study are to establish whether lower baseline vitamin D levels are associated with greater functional limitation and faster rates of functional decline as compared to higher baseline vitamin D levels in men and women with PAD. In our secondary and exploratory study aims, we will identify mechanisms of associations of low vitamin D levels with impaired functional performance and faster functional decline, by determining whether lower vitamin D levels are associated with more adverse calf skeletal muscle characteristics, poorer lower extremity strength, poorer lower extremity peripheral nerve function, and higher inflammatory biomarker levels in persons with PAD. Our study aims will be tested in our well characterized National Heart Lung and Blood Institute-funded Walking and Leg Circulation Study II (WALCS II) cohort of men and women age 59 and older. WALCS II includes 414 participants with PAD who were followed for up to four years and have stored, frozen blood available for vitamin D measurement. WALCS II participants underwent baseline and annual measurement of functional performance, lower extremity strength, and biomarkers. Computed tomography was used to measure calf muscle characteristics at baseline and follow-up visits. Lower extremity peripheral nerve function was also measured. Patients with PAD may be particularly susceptible to the adverse consequences of low vitamin D levels, because lower extremity ischemia is associated with adverse calf skeletal muscle characteristics which in turn promotes functional decline in patients with PAD. For a low marginal cost, this proposed study will determine whether a clinical trial (in subsequent study) is warranted to determine whether vitamin D supplementation improves functional performance and prevents functional decline in persons with PAD. Our proposed study will also identify the outcomes and mediators to measure in a randomized controlled clinical trial of vitamin D therapy for patients with PAD. PUBLIC HEALTH RELEVANCE: Vitamin D levels are declining among adults in the United States and the clinical consequences of these declines are unclear. The current study will establish whether low baseline vitamin D levels are associated with greater functional limitation and faster functional decline compared to higher vitamin D levels in persons with PAD.